Human immunodeficiency virus (HIV-1) is the major etiologic agent of acquired immunodeficiency syndrome (AIDS) in humans. Measures to block the early events in HIV-1infection are needed to treat infected individuals and to prevent virus transmission. HIV-1 entry into host cells, which is mediated by the viral envelope glycoproteins, represents an attractive target for intervention. The HIV-1 envelope glycoproteins, gp120 and gp41, are assembled into trimeric complexes on the virion surface. The gp120 exterior envelope glycoprotein mediates virus attachment to target cell receptors, CD4 and chemokine receptors. CD4 binding triggers conformational changes in gp120 that allow chemokine receptor binding and exposure of the gp41 transmembrane envelope glycoprotein. Ultimately, gp41 mediates the fusion of the viral and target cell membranes, completing the virus entry process. Small-molecule and peptide ligands of gp120 have been discovered that can act as agonists or antagonists of HIV-1 entry. Agonists, of which NBD-556 is the prototype, mimic CD4 and activate chemokine receptor binding and entry. A major goal of this Program is to modify gp120 agonists to create chemical antagonists of HIV-1 entry. Antagonists either induce non-productive conformations in gp120 or block conformational transitions of the envelope glycoproteins important for HIV-1 entry. In the course of this Program, analogues of these prototypes will be designed and synthesized. The specific aims of this project are: 1) To test the effect of candidate compounds on the entry of HIV-1; 2) To investigate the binding site of the compounds on the HIV-1 gp120 glycoprotein; 3) To elucidate the mechanism of inhibition of HIV-1 entry by the compounds; 4) To understand the impact of variation in the HIV-1 envelope glycoproteins on the antiviral efficacy of the compounds.